Visceral obesity and the metabolic syndrome are global public health problems. Adipose tissue-specific glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenases (11betaHSDs) has been implicated in the pathogenesis of these disorders. 11betaHSDs are enzymes that catalyze the inter-conversion between active glucocorticoids (GCs) and their inactive 11-keto metabolites in a tissue-specific manner. The type 1 isoform (11betaHSD1) activates GCs while the type 2 isoform (11betaHSD2) inactivates GCs. The central aim of this proposal is to determine the role of adipocyte-specific GC metabolism by 11betaHSDs in key metabolic processes involved in energy homeostasis and the regulation of body weight. Aim #1 proposes to create a transgenic mouse model of adipocyte-specific GC inactivation by 11betaHSDs. This aim will be accomplished through transgenic overexpression of human 11betaHSD2 under the control of the murine aP2 promoter/enhancer (aP2-h11betaHSD2). Aim #2 investigates whether adipocyte-specific GC inactivation will prevent or ameliorate diet-induced and genetic forms of rodent obesity. This aim will be accomplished through transgenic overexpression of aP2-h11betaHSD2 in 1) mouse strains differing in susceptibility to diet-induced obesity when fed a high fat diet, and 2) well-established models of genetic obesity such as leptin-deficient Lepob/Lepob mice. Aim #3 explores the adipocyte-specific regulation of 11betaHSD1 by leptin, melanocortin, and beta adrenergic pathways. This proposal is designed to facilitate the training and career development of the applicant in the field of obesity and metabolism, specifically in the biology of adipocytes and their contribution to metabolic disorders. The career development plan includes the main research project, laboratory technique training, laboratory meetings, data presentations, mentor meetings, didactic seminars, and scientific meetings. The proposed research will take place in the Division of Endocrinology, Diabetes, and Metabolism at Beth Israel Deaconess Medical Center where all the resources (equipment, technical expertise) to carry out the proposed research are readily available. The ultimate goal is for the applicant to become an independent investigator.